Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells

Zhou, Zhiwei; He, Hongbin; Wang, Kun; Shi, Xuyan; Wang, Yupeng; Su, Ya; Wang, Yao; Li, Da; Liu, Wang; Zhang, Yongliang; Shen, Lianjun; Han, Weidong; Shen, Lin; Ding, Jingjin; Shao, Feng

doi:10.1126/science.aaz7548

Cited by 914 publications

(930 citation statements)

References 59 publications

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“…This indicated that we could not exclude the pyroptotic role of other members of the gasdermin family, like GSDMA, GSDMB, and GSDME, which also display pore-forming and pyroptotic activity. [40][41][42] Further analysis revealed that PPE13 was localized to the surface of cells, which is consistent with results of a previous study. 20 The presence of PE/PPE proteins on the cell surface might enable them to directly interfere with host innate immune pathways.…”

Section: F I G U R E 4 Ppe13supporting

confidence: 91%

Mycobacterial PPE13 activates inflammasome by interacting with the NATCH and LRR domains of NLRP3

Yang

et al. 2020

FASEB j.

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Pathogenic mycobacteria, such as Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium marinum, can trigger NLRP3 inflammasome activation leading to maturation and secretion of interleukin 1β (IL‐1β). However, the mycobacterial factors involved in the activation of NLRP3 inflammasome are not fully understood. Here, we identified that the PPE family protein PPE13 was responsible for the induction of IL‐1β secretion in a NLRP3 inflammasome‐dependent manner. We found that the recombinant Mycobacterium smegmatis expressing PPE13 activates NLRP3 inflammasome, thereby inducing caspase‐1 cleavage and IL‐1β secretion in J774A.1, BMDMs, and THP‐1 macrophages. To examine whether this inflammasome activation was triggered by PPE13 rather than components of M. smegmatis, PPE13 was introduced into the aforementioned macrophages by lentivirus as a delivery vector. Similarly, this led to the activation of NLRP3 inflammasome, indicating that PPE13 is a direct activator of NLRP3 cascade. We further demonstrated that the NLRP3 complex activated the inflammasome cascade, and the assembly of this complex was facilitated by PPE13 through interacting with the LRR and NATCH domains of NLRP3. Finally, we found that all PPE13 proteins isolated from M. tuberculosis, M. bovis, and M. marinum can activate NLRP3 inflammasome through binding to NLRP3, which requires C‐terminal repetitive MPTR domain of PPE13. Thus, we, for the first time, revealed that PPE13 triggers the inflammasome‐response by interacting with the MPTR domain of PPE13 and the LRR and NATCH domains of NLRP3. These findings provide a novel perspective on the function of PPE proteins in the immune system during mycobacteria invasion.

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Section: F I G U R E 4 Ppe13supporting

confidence: 91%

Mycobacterial PPE13 activates inflammasome by interacting with the NATCH and LRR domains of NLRP3

Yang

et al. 2020

FASEB j.

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“…This study centers on the experimental broad-spectrum DPP inhibitor BXCL701 (also named VbP, PT-100, or Talabostat) that was recently assigned orphan drug designation for the treatment of AML by the FDA, and is based on recent findings showing that VbP/BXCL701 and more selective DPP8/DPP9 inhibitors are potent inducers of pyroptosis in AML cell lines and in primary AML samples from patients. 164 Several recent studies showed that enforced activation of Gasdermin family members in cancer cells enhanced immune cell-mediated tumor clearance in mouse models, [165][166][167] adding credence to the notion that pyroptosis induction may enhance cancer immunotherapies to the benefit of patients.…”

Section: G S Dmd -The Ne W K Id On the B Lo Ckmentioning

confidence: 98%

Therapeutic modulation of inflammasome pathways

Chauhan

Walle

Lamkanfi

2020

Immunological Reviews

158

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Inflammasomes are macromolecular complexes formed in response to pathogen‐associated molecular patterns (PAMPs) and danger‐associated molecular patterns (DAMPs) that drive maturation of the pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐18, and cleave gasdermin D (GSDMD) for induction of pyroptosis. Inflammasomes are highly important in protecting the host from various microbial pathogens and sterile insults. Inflammasome pathways are strictly regulated at both transcriptional and post‐translational checkpoints. When these checkpoints are not properly imposed, undue inflammasome activation may promote inflammatory, metabolic and oncogenic processes that give rise to autoinflammatory, autoimmune, metabolic and malignant diseases. In addition to clinically approved IL‐1‐targeted biologics, upstream targeting of inflammasome pathways recently gained interest as a novel pharmacological strategy for selectively modulating inflammasome activation in pathological conditions.

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“…In addition, our results employing an inhibitor of extracellular GzmA, Serpinb6b, in vitro and in vivo, strongly suggest that GzmA enhances the inflammatory pathological response in sepsis in the extracellular space. Thus, since Serpinb6b should not affect intracellularly perforindelivered GzmA, we suggest that GzmA does not contribute to sepsis by promoting pyroptosis (Zhou et al, 2020) or other types of cell death (Susanto et al, 2013). This suggestion is further supported by our results showing increased levels of extracellular GzmA in serum from patients with abdominal sepsis.…”

Section: Discussionmentioning

confidence: 83%

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Arias

Pardo

Garzón

et al. 2020

Preprint

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Sepsis is a serious syndrome characterised by a dysregulated systemic inflammatory response. Here we have analysed the role and the therapeutic potential of Granzyme A (GzmA) in the pathogenesis of peritoneal sepsis using the Cecal Ligation and Puncture (CLP) polymicrobial sepsis model and samples from humans undergoing abdominal sepsis.Elevated GzmA was observed in serum from patients with abdominal sepsis suggesting that GzmA plays an important role in this pathology. In the CLP model GzmA deficient mice, or WT mice treated with an extracellular GzmA inhibitor, showed increased survival, which correlated with a reduction in proinflammatory markers in both serum and peritoneal lavage fluid. GzmA deficiency did not influence bacterial load in blood and spleen indicating that GzmA has no role in bacterial control.Mechanistically, we found that extracellular active GzmA acts as a proinflammatory mediator in macrophages by inducing the TLR4-dependent expression of IL-6 and TNFα.Our findings implicate GzmA as a key regulator of the inflammatory response during abdominal sepsis, and suggest that it could be targeted for treatment of this severe pathology.

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Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells

Cited by 914 publications

References 59 publications

Mycobacterial PPE13 activates inflammasome by interacting with the NATCH and LRR domains of NLRP3

Mycobacterial PPE13 activates inflammasome by interacting with the NATCH and LRR domains of NLRP3

Therapeutic modulation of inflammasome pathways

Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

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